Structural insight into acute intermittent porphyria

Song, Gaojie; Li, Yang; Cheng, Chu Yong; Zhao, Yu; Gao, Ang; Zhang, Rongguang; Joachimiak, Andrzej; Shaw, Neil; Liu, Zhijie

doi:10.1096/fj.08-115469

Cited by 45 publications

(91 citation statements)

References 35 publications

(39 reference statements)

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“…Lysine at position 98 has previously been demonstrated to mutate to arginine,12 but we show a change to glutamic acid (p.Lys98Glu) in two Caucasian patients. This invariant lysine moiety is located within the active site cleft and in close proximity to the DPM cofactor, and forms salt bridges with the acetate cofactor side chains 35. Kinetic studies using wild-type HMBS reveal a K M (8.49 μM) similar to that previously described (8.7 μM) 36.…”

Section: Discussionsupporting

confidence: 69%

Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

et al. 2016

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Section: Discussionsupporting

confidence: 69%

Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

et al. 2016

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“…The role of these residues in catalysis and substrate binding was confirmed by site-directed mutagenesis. Since then, the structures of a number of HmbSs have been determined, including those of Arabidopsis, human, and Bacillus megaterium, revealing similar overall topologies (132)(133)(134)(135). Interestingly, no one has been able to grow crystals of the enzyme in the presence of a substrate, so it is not known how the growing polypyrrole product is held within the active site of the enzyme or how the domains of the enzyme move during the catalytic process.…”

Section: Dailey Et Almentioning

confidence: 99%

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

Dailey

Gerdes³

et al. 2017

Microbiol Mol Biol Rev

246

329

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SUMMARY The advent of heme during evolution allowed organisms possessing this compound to safely and efficiently carry out a variety of chemical reactions that otherwise were difficult or impossible. While it was long assumed that a single heme biosynthetic pathway existed in nature, over the past decade, it has become clear that there are three distinct pathways among prokaryotes, although all three pathways utilize a common initial core of three enzymes to produce the intermediate uroporphyrinogen III. The most ancient pathway and the only one found in the Archaea converts siroheme to protoheme via an oxygen-independent four-enzyme-step process. Bacteria utilize the initial core pathway but then add one additional common step to produce coproporphyrinogen III. Following this step, Gram-positive organisms oxidize coproporphyrinogen III to coproporphyrin III, insert iron to make coproheme, and finally decarboxylate coproheme to protoheme, whereas Gram-negative bacteria first decarboxylate coproporphyrinogen III to protoporphyrinogen IX and then oxidize this to protoporphyrin IX prior to metal insertion to make protoheme. In order to adapt to oxygen-deficient conditions, two steps in the bacterial pathways have multiple forms to accommodate oxidative reactions in an anaerobic environment. The regulation of these pathways reflects the diversity of bacterial metabolism. This diversity, along with the late recognition that three pathways exist, has significantly slowed advances in this field such that no single organism's heme synthesis pathway regulation is currently completely characterized.

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“…A few mouse IRGB proteins are linked in tandem to contain two Rashomology domains, but these retain the homodimerization motifs (Lilue et al 2013), while the mouse Irga6 protein dimerizes in a head-to-head fashion (Schulte et al 2016). Intriguingly, the two C. elegans Ras-like domains are separated by a region with homology to a central hinge domain of porphobilinogen deaminase (Louie et al 1992;Song et al 2009), a member of the PBP2 superfamily found in all creatures from bacteria to humans (Shoolingin-Jordan 1995). In many of these enzymes, the hinge is located between two ATPase domains which, when activated, bind to substrate.…”

Section: Exc-1 As a Model For Mammalian Irg Proteinsmentioning

confidence: 99%

Facilitation of Endosomal Recycling by an IRG Protein Homolog Maintains Apical Tubule Structure in Caenorhabditis elegans

et al. 2016

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Determination of luminal diameter is critical to the function of small single-celled tubes. A series of EXC proteins, including EXC-1, prevent swelling of the tubular excretory canals in Caenorhabditis elegans. In this study, cloning of exc-1 reveals it to encode a homolog of mammalian IRG proteins, which play roles in immune response and autophagy and are associated with Crohn's disease. Mutants in exc-1 accumulate early endosomes, lack recycling endosomes, and exhibit abnormal apical cytoskeletal structure in regions of enlarged tubules. EXC-1 interacts genetically with two other EXC proteins that also affect endosomal trafficking. In yeast two-hybrid assays, wild-type and putative constitutively active EXC-1 binds to the LIM-domain protein EXC-9, whose homolog, cysteine-rich intestinal protein, is enriched in mammalian intestine. These results suggest a model for IRG function in forming and maintaining apical tubule structure via regulation of endosomal recycling. KEYWORDS tubulogenesis; trafficking; endosomes; IRG; immunity-related GTPase S MALL tubules are fundamental structures found in a wide range of tissues in multicellular organisms (Lubarsky and Krasnow 2003;Sigurbjornsdottir et al. 2014). Luminal diameter regulation occurs after initial tubule formation; mutations exist in a range of species in which tubes form initially, but cannot maintain their luminal diameter, and change shape over times ranging from minutes for some Caenorhabditis elegans mutants to decades for some forms of Schwann cell degradation (Patzko and Shy 2012). The mechanisms of maintenance of tube diameter as animals age and grow are still relatively unknown. Mechanosensitive channels on primary cilia projecting into the lumen regulate luminal diameter in multicellular tubes such as blood vessels, nephrons, and biliary ducts (Ware et al. 2011;Martinac 2014), but narrower single-celled tubules such as those of myelinating Schwann cells do not express cilia on their luminal surface (Yoshimura and Takeda 2012).The C. elegans excretory canal cell provides a tractable genetic model for investigating maintenance of luminal diameter in a seamless single-celled tube (Buechner 2002;Sundaram and Buechner 2016). The excretory canal cell is born in midembryogenesis, forms a hollow lumen, and extends both leftward and rightward to the lateral surface, where each side branches and extends canals both anteriorward and posteriorward to form an "H"-shaped structure (Chitwood and Chitwood 1974;Sulston et al. 1983) ( Figure 1A). Once formed, the excretory canals must continue to grow along with the animal. The diameter is tightly controlled, as the lumens taper toward their closed-tip distal ends and expand as the animal ages (Nelson et al. 1983;Sundaram and Buechner 2016). The luminal membrane is surrounded by a thick terminal web similar in appearance to that of intestinal cells and is rich in vacuolar ATPase (Nelson et al. 1983;Oka et al. 1997). Posterior canal extends full-length to the tip of the animal and is of normal diameter, indicat...

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Structural insight into acute intermittent porphyria

Cited by 45 publications

References 35 publications

Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

Molecular characterisation of acute intermittent porphyria in a cohort of South African patients and kinetic analysis of two expressed mutants

Prokaryotic Heme Biosynthesis: Multiple Pathways to a Common Essential Product

Facilitation of Endosomal Recycling by an IRG Protein Homolog Maintains Apical Tubule Structure in Caenorhabditis elegans

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